Olefin metathesis is an efficient reaction for the formation of carbon-carbon bonds by exchanging substituent groups on two olefin reactants. Certain ruthenium catalysts have helped to increase the practicality of using olefin metathesis for organic synthesis due to modified functional groups that have increased the tolerance of the complexes to air and moisture. However, highly active catalysts can be sensitive to some polar functional groups, while catalysts that are more stable with respect to polar functional groups can have diminished activity. Therefore, preferred metathesis catalysts are those that are more stable to functional groups while retaining substantially undiminished activity. There is also a need in the art for improved synthetic processes that can be carried out using such catalysts.
I. A,B-Alternating Copolymers and Derivatives
Interest in making well-defined linear polymers substituted with polar and/or functional groups has been spurred, in large part, by the widespread commercial utility of functionalized olefinic polymers. For example, ethylene-vinyl alcohol (EVOH) copolymers. EVOH copolymers, as a class, exhibit excellent barrier properties toward gases and hydrocarbons and have found use in the food packaging, biomedical, and pharmaceutical industries. See Lagaron et al. (2001) Polym. Testing 20:569-577, and Ramakrishnan (1991) Macromolecules 24:3753-3759.
Alternating copolymers are normally formed by step growth polymerization of AA-BB monomers and in some special chain-growth reactions (for example, in the synthesis of A,B-polyaminoacids). Although recent developments in ring-opening metathesis polymerization (ROMP) (e.g., U.S. Pat. No. 6,482,908) and acyclic-diene-metathesis polymerization (ADMET) (e.g., Wagener et al. (1990) Makromol. Chem. 191: 365-374, regarding ADMET polymerization of vinyl terminated oligo-octenylenes using a Lewis acid-free catalyst) have extended the versatility of both chain-growth and step-growth reactions, these metathesis polymerization reactions have not provided a general solution to alternating co-polymerization. Examples of alternating copolymers prepared by ROMP are rare as a result of the difficulty of finding systems in which there is an alternation in the affinity of the metal carbene for the monomers. Although ADMET is a step-growth polymerization, examples of alternating co-polymerization with two monomers by this mechanism have not been reported since most olefins studies have similar reactivity. Therefore, a general metathesis route toward A,B-alternating copolymers would open the way to the synthesis of new functional polymers.
The direct incorporation of polar functional groups along the backbone of linear polymers made via ring-opening metathesis polymerization is now possible due to the development of functional group-tolerant late transition metal olefin metathesis catalysts. Recently, Hillmyer et al. reported the ROMP of alcohol-, ketone-, halogen-, and acetate-substituted cyclooctenes with a ruthenium olefin metathesis catalyst (Hillmyer et al. (1995) Macromolecules 28: 6311-6316). However, the asymmetry of the substituted cyclooctene allowed for head-to-head (HH), head-to-tail (HT), and tail-to-tail (TT) coupling, yielding polymer with regiorandom placement of the functional groups. A similar problem was encountered by Chung et al., who reported the ROMP of a borane-substituted cyclooctene with an early transition metal catalyst followed by oxidation to yield an alcohol functionalized linear polymer (Ramakrishnan et al. (1990), supra). A solution to this regiorandom distribution of functional groups was reported by Valenti et al., who used the acyclic diene metathesis (ADMET) polymerization of an alcohol-containing symmetric diene (Valenti et al., supra; Schellekens et al. (2000) J. Mol. Sci. Rev. Macromol. Chem. Phys. C40:167-192)) However, the molecular weights of these polymers were restricted to <3×104 g/mol by ADMET, and their rich hydrocarbon content limits the barrier properties of the final EVOH copolymers (Lagaron et al., supra).
Accordingly, there is a need to provide an improved and efficient method for producing regioregular A,B-polymers. There is also a need for such regioregular olefin polymers that might be modified further by modifying functional groups in a regioregular or regiorandom manner. Another need is to provide a method that would permit producing derivatives from such A,B-regioregular polymers (e.g., A,C-polymers or AB,AC polymers in a regioregular or regiorandom manner) by direct insertion of monomer units into the polymer backbone.
II. Transition Metal Carbene Complexes as Metathesis Catalysts
Transition metal carbene complexes, particularly ruthenium and osmium carbene complexes, have been described as metathesis catalysts in U.S. Pat. Nos. 5,312,940, 5,342,909, 5,831,108, 5,969,170, 6,111,121, and 6,211,391 to Grubbs et al., assigned to the California Institute of Technology. The ruthenium and osmium carbene complexes disclosed in these patents all possess metal centers that are formally in the +2 oxidation state, have an electron count of 16, and are penta-coordinated. Such complexes have been disclosed as useful in catalyzing a variety of olefin metathesis reactions, including ROMP, ring closing metathesis (“RCM”), ADMET, ring-opening metathesis (“ROM”), and cross-metathesis (“CM” or “XMET”) reactions. Examples of such catalysts are (PCy3)2(Cl)2Ru═CHPh (1) and (IMesH2)(PCy3)(Cl)2Ru═CHPh (2): 
In the above molecular structures, “Mes” represents mesityl (2,4,6-trimethylphenyl), “Ph” is phenyl, and “Cy” is cyclohexyl.
Catalysts (1) and (2) have been shown to afford the ROMP of many substituted cyclic olefins. See, for example, Bielawski et al. (2000) Angew. Chem., Int. Ed. 39:2903-2906; Sanford et al. (2001) J. Am. Chem. Soc. 123:6543-6554; Amir-Ebrahimi et al. (2000) Macromolecules 33:717-724; and Hamilton et al. (2000) J. Organomet. Chem 606:8-12. Recent development of ruthenium catalysts, such as (2), coordinated with an N-heterocyclic carbene has allowed for the ROMP of low-strain cyclopentene and substituted cyclopentene. Bielawski et al., supra. The ROMP of a symmetric cyclopentene yields a regioregular polyalkene, as no difference exists between HH, HT, and TT couplings. Hence, the ROMP of alcohol- or acetate-disubstituted cyclopentene monomers was attempted (Scheme 1). 
Unfortunately, neither catalyst (1) nor the more active (2) could afford the ROMP of these cyclopentene monomers under ordinary reaction conditions. Therefore, co-pending patent application Ser. No. 10/232,105, filed Aug. 29, 2002, entitled “Ring-Opening Metathesis Polymerization of Bridged Bicyclic and Polycyclic Olefins Containing Two or More Heteroatoms,” provides a polymerization process utilizing protection and deprotection processes.
Accordingly, there is a need in the art for improved methods of synthesizing regioregular A,B-polymers and their derivatives, using catalysts that are tolerant of functional groups and a process that enables precise controls over the resulting products and structural distribution of functional groups in the molecules produced. Ideally, such a method would also be useful in the synthesis of regioregular and/or telechelic A,B-polymers. The invention is directed to such methods, and now provides a highly effective process using a transition metal carbene complex such as (1) or (2). The processes can be used to synthesize regioregular and/or telechelic A,B-polymers, in a manner that enables careful control over the macrocycles and polymer properties, as well as derivatives thereof.